Processes for the preparation of pesticidal compounds

ABSTRACT

The present application provides processes for making pesticidal compounds and compounds useful both as pesticides and in the making of pesticidal compounds.

CROSS REFERENCE TO RELATED APPLICATIONS

This application claims the benefit of the following U.S. ProvisionalPatent Applications: Ser. No. 62/043,040, filed Aug. 28, 2014; and Ser.No. 61/892,127, filed Oct. 17, 2013, the entire disclosure of theseapplications are hereby expressly incorporated by reference into thisApplication.

TECHNICAL FIELD

This application relates to efficient and economical synthetic chemicalprocesses for the preparation of pesticidal thioether and pesticidalsulfoxides. Further, the present application relates to certain novelcompounds necessary for their synthesis. It would be advantageous toproduce pesticidal thioether and pesticidal sulfoxides efficiently andin high yield from commercially available starting materials.

DETAILED DESCRIPTION

The following definitions apply to the terms as used throughout thisspecification, unless otherwise limited in specific instances.

As used herein, the term “alkyl” denotes branched or unbranchedhydrocarbon chains.

As used herein, the term “alkynyl” denotes branched or unbranchedhydrocarbon chains having at least one C≡C.

Unless otherwise indicated, the term “cycloalkyl” as employed hereinalone is a saturated cyclic hydrocarbon group, such as cyclopropyl,cyclobutyl, cyclopentyl, cyclohexyl.

The term “thio” as used herein as part of another group refers to asulfur atom serving as a linker between two groups.

The term “halogen” or “halo” as used herein alone or as part of anothergroup refers to chlorine, bromine, fluorine, and iodine.

The compounds and process of the present application are described indetail below in scheme 1.

In step a of Scheme 1, 4-nitropyrazole is halogenated and reduced toyield 3-chloro-1H-pyrazol-4-amine hydrochloride (1a). The halogenationoccurs at the 3-carbon through the use of concentrated (37 weightpercent) hydrochloric acid (HCl). The reduction occurs withtriethylsilane (Et₃SiH) and palladium on alumina (Pd/Al₂O₃, preferablyabout 1 to 10 weight percent palladium on alumina, more preferably about5 weight percent). This reaction may be conducted at a temperature fromabout 0° C. to about 40° C., preferably about 10° C. to about 20° C.This reaction may be conducted in a polar protic solvent, such asmethanol (MeOH) or ethanol (EtOH), preferably ethanol. It wassurprisingly discovered, that by utilizing about 1 equivalents to about4 equivalents, preferably, about 2.5 equivalents to about 3.5equivalents of triethylsilane in this step, while conducting thereaction between about 10° C. and about 20° C., gives about a 10:1 molarratio of the desired halogenated product 3-chloro-1H-pyrazol-4-aminehydrochloride (1a)

versus the undesired product

In step b of Scheme 1, 3-chloro-1H-pyrazol-4-amine hydrochloride (1a) isreacted with between about 1 equivalent and about 2 equivalents of3-chloropropionyl chloride in the presence of a base, preferably, metalcarbonates, metal hydroxides, metal phosphates, more preferably sodiumbicarbonate (NaHCO₃) to yield3-chloro-N-(-3-chloro-1H-pyrazol-4-yl)propanamide (4a). The reaction maybe conducted in a mixture of tetrahydrofuran (THF), and water. It wassurprisingly discovered that a chloro substituent must be present at the3-position for this reaction to proceed to completion and to also avoidover acylation. Described herein is a comparative example without ahalogen at the 3-position that yielded the double acylated product (see“CE-1”). Further, comparative example with a bromo group at the3-position afforded the product in a surprisingly low yield compared tothe yield with the chloro group (see “CE-2”).

In step c of Scheme 1, 3-chloro-N-(-3-chloro-1H-pyrazol-4-yl)propanamide(4a) undergoes nucleophilic substitution by a thiol (HS-R¹), in thepresence of an inorganic base, preferably, metal carbonates, metalhydroxides, metal phosphates, metal hydrides, more preferably, potassiumhydroxide, conducted in the presence of a polar solvent, preferablymethanol, wherein R¹ is selected from the group consisting ofC₁-C₄-haloalkyl and C₁-C₄-alkyl-C₃-C₆-halocycloalkyl, preferably, R¹ isselected from CH₂CH₂CF₃ or CH₂(2,2-difluorocyclopropyl) to yieldthioether (4b).

In step d of Scheme 1, thioether (4b) is reacted with a halopyridine,preferably, 3-bromopyridine in the presence of a copper salt, (such ascopper(I) chloride (CuCl), copper(II) chloride (CuCl₂) or copper(I)iodide (Cul)), a base such as potassium phosphate (K₃PO₄), or potassiumcarbonate (K₂CO₃), preferably potassium carbonate, andN,N′-dimethylethane-1,2-diamine to yield amide (4c). This syntheticmethod is simpler and reduces the costs of starting materials over knownheteroarylation methods. The process may be conducted in a polarsolvent, such as, acetonitrile (MeCN), dioxane, or N,N-dimethylformamideat a temperature between about 50° C. and about 110° C., preferablybetween about 70° C. and about 90° C. It is preferred that the reactionmixture is stirred with heating for between 2 hours and 24 hours.

In step e of Scheme 1, pesticidal thioether (4c) is alkylated preferablywith a R²—X² to yield pesticidal thioether (4d), wherein X² is a leavinggroup. The leaving group may be selected from halo, mesylate, ortosylate. R² is selected from C₁-C₄-alkyl, C₂-C₄-alkynyl, preferably,methyl, ethyl, and propargyl. R²—X² may be selected from methyl iodide,ethyl bromide, ethyl iodide, propargyl chloride, propargyl bromide,ethyl mesylate, propargyl mesylate, ethyl tosylate, and propargyltosylate. The alkylation is conducted in the presence of an inorganicbase, preferably, metal carbonates, metal hydroxides, metal phosphates,metal hydrides, more preferably, cesium carbonate (Cs₂CO₃), conducted inthe presence of a polar solvent, preferably N,N-dimethylformamide (DMF)at temperatures from about 0° C. to about 50° C.

Alternatively, in step e of Scheme 1, the alkylation of pesticidalthioether (3b) may be conducted in the presence of a base such as sodiumhydride (NaH), in the presence of a polar aprotic solvent, such asN,N-dimethylformamide, tetrahydrofuran, hexamethylphosphoramide (HMPA),dimethylsulfoxide (DMSO), N-methyl-2-pyrrolidinone (NMP), and sulfolane,at temperatures from about 0° C. to about 50° C. It has beenunexpectedly discovered that the use of sulfolane as solvent promotesthe alkylation reaction over the competitive retro-Michael-typeelimination of the C₁-C₄-alkyl-S—R′unit (see “CE-3”). It has beendiscovered that the catalytic use of an additive, such as potassiumiodide (KI) or tetrabutylammonium iodide (TBAI) decreases the timenecessary for the reaction to occur to about 24 hours.

In step f of Scheme 1, thioether (4d) is oxidized with hydrogen peroxide(H₂O₂) in methanol to yield the desired pesticidal sulfoxide (4e).

EXAMPLES

The following examples are presented to better illustrate the processesof the present application.

Example 1 3-chloro-1H-pyrazol-4-amine hydrochloride (1a)

A 1000-mL, multi-neck cylindrical jacketed reactor, fitted with amechanical stirrer, temperature probe and nitrogen (N₂) inlet, wascharged with 4-nitropyrazole (50.0 g, 429 mmol) and palladium on alumina(5 wt %, 2.5 g). Ethanol (150 mL) was added, followed by a slow additionof concentrated hydrochloric acid (37 wt %, 180 mL). The reaction wascooled to 15° C., and triethylsilane (171 mL, 1072 mmol) was addedslowly via addition funnel over 1 hour, while maintaining the internaltemperature at 15° C. The reaction was stirred at 15° C. for 72 hours,after which the reaction mixture was filtered through a Celite® pad andthe pad was rinsed with warm ethanol (40° C., 2×100 mL). The combinedfiltrates were separated and the aqueous layer (bottom layer) wasconcentrated to ˜100 mL. Acetonitrile (200 mL) was added and theresulting suspension was concentrated to ˜100 mL. Acetonitrile (200 mL)was added and the resulting suspension was concentrated to ˜100 mL.Acetonitrile (200 mL) was added and the resulting suspension was stirredat 20° C. for 1 hour and filtered. The filter cake was rinsed withacetonitrile (2×100 mL) and dried under vacuum at 20° C. to afford awhite solid (˜10:1 mixture of 1a and 1H-pyrazole-4-amine, 65.5 g, 99%):¹H NMR (400 MHz, DMSO-d₆) δ 10.52 (bs, 3H), 8.03 (s, 1H) EIMS m/z 117([M]⁺).

Example 2 3-chloro-N-(-3-chloro-1H-pyrazol-4-yl) propanamide (4a)

A 250-mL 3-neck flask was charged with3-chloro-1H-pyrazol-4-amine-hydrochloride (10.0 g, 64.9 mmol),tetrahydrofuran (50 mL), and water (50 mL). The resulting suspension wascooled to 5° C. and sodium bicarbonate (17.6 g, 210 mmol) was added,followed by dropwise addition of 3-chloropropanoyl chloride (7.33 g,57.7 mmol) at <5° C. The reaction was stirred at <10° C. for 1 hour, atwhich point thin layer chromatography (TLC) [Fluent: 1:1 ethyl acetate(EtOAc)/hexane] analysis indicated the starting material was consumedand the desired product was formed. It was diluted with water (50 mL)and ethyl acetate (50 mL) and the layers separated. The aqueous layerwas extracted with ethyl acetate (20 mL) and the combined organic layerswere concentrated to dryness to afford a pale brown solid, which waspurified by flash column chromatography using ethyl acetate as eluent.The pure fractions were concentrated to afford a white solid (9.20 g,77%): mp: 138-140° C.; ¹H NMR (400 MHz, DMSO-d₆) δ 12.91 (s, 1H), 9.68(s, 1H), 8.03 (d, J=1.7 Hz, 1H), 3.85 (t, J=6.3 Hz, 2H), 2.8.5 (t, J=6.3Hz, 2H); ¹³C NMR (101 MHz, DMSO-d₆) δ 167.52, 130.05, 123.59, 116.48,40.75, 37.91; EIMS m/z 207 ([M]⁺).

Example 3N-(3-chloro-1H-pyraxol-4-yl)-3-((3,3,3,trifluoropropyl)thio)propanamide(Compound 3.4)

A 100 mL, 3-neck round bottom flask was charged with3-chloro-N-(3-chloro-1H-pyrazol-4-yl)propanamide (1.00 g, 4.81 mmol) andmethanol (10 mL), potassium hydroxide (KOH, 0.324 g, 5.77 mmol) wasadded, followed by 3,3,3-trifluoropropane-1-thiol (0.751 g, 5.77 mmol).The mixture was heated at 50° C. for 4 hours, at which point thin layerchromatography analysis [Fluent: ethyl acetate] indicated that thereaction was complete to give exclusively a new product. It was cooledto 20° C. and diluted with water (20 mL) and ethyl acetate (20 mL). Thelayers were separated and the aqueous layer was extracted with ethylacetate (20 mL). The organic layers were combined and dried over sodiumsulfate (Na₂SO₄) and concentrated to dryness to afford a light yellowoil, which was purified by flash column chromatography using 40% ethylacetate/hexanes as eluent to afford a white solid after concentration(1.02 g, 70%): mp 83-85° C.; ¹H NMR (400 MHz, DMSO-d₆) δ 12.90 (s, 1H),9.59 (s, 1H), 8.02 (s, 1H), 2.82 (t, J=7.2 Hz, 2H), 2.76-2.69 (m, 2H),2.66 (t, J=7.1 Hz, 2H), 2.62-2.48 (m, 2H); ¹³C NMR (101 MHz, DMSO-d₆) δ168.97, 129.95, 126.60 (q, J=277.4 Hz), 123.42, 116.60, 35.23, 33.45 (q,J=27.3 Hz), 26.85, 23.03 (q, J=3.4 Hz); EIMS m/z 301 ([M]⁺).

Example 4N-(3-chloro-1-(pyridin-3-yl)-1H-pyrazol-4-yl)-3-((3,3,3-trifluoropropyl)thio)propanamide(Compound 4.4)

A 100 mL, 3-neck round bottom flask was charged with copper(I) iodide(0.343 g, 1.80 mmol), acetonitrile (50 mL),N,N′-dimethylethane-1,2-diamine (0.318 g, 3.61 mmol),N-(3-chloro-1H-pyrazol-4-yl)-3-((3,3,3-trifluoropropyl)thio)propanamide(2.72 g, 9.02 mmol), potassium carbonate (2.49 g, 18.0) and3-bromopyridine (1.71 g, 10.8 mmol). The mixture was purged withnitrogen three times and heated to 80° C. for 4 hours, at which pointthin layer chromatography analysis [Eluent: ethyl acetate] indicatedthat only a trace of starting material remained. The mixture wasfiltered through a Celite® pad and the pad was rinsed with acetonitrile(20 mL). The filtrates were concentrated to dryness and the residue waspurified by flash column chromatography using 0-100% ethylacetate/hexanes as eluent. The fractions containing pure product wereconcentrated to dryness and further dried under vacuum to afford a whitesolid (1.82 g, 53%): mp 99-102° C.; ¹H NMR (400 MHz, DMSO-d₆) δ 9.92 (s,1H), 9.05 (d, J=2.7 Hz, 1H), 8.86 (s, 1H), 8.54 (dd, J=4.5, 1.4 Hz, 1H),8.21 (ddd, J=8.4, 2.7, 1.4 Hz, 1H), 7.54 (dd, J=8.4, 4.7 Hz, 1H), 2.86(t, J=7.3 Hz, 2H), 2.74 (td, J=6.5, 5.6, 4.2 Hz, 4H), 2.59 (ddd, J=11.7,9.7, 7.4 Hz, 2H); ¹³C NMR (101 MHz, DMSO-d₆) δ 169.32, 147.49, 139.44,135.47, 133.40, 126.60 (q, J=296 Hz), 125.49, 124.23, 122.30, 120.00,35.18, 33.42 (q, J=27.2 Hz), 26.77, 2105 (q, J=3.3 Hz); EIMS m/z 378(w).

Example 5N-(3-chloro-1-(pyridin-3-yl)-1H-pyrazol-4-yl)-N-ethyl-3-((3,3,3-trifluoropropyl)thio)propanamide(Compound 5.4)

A 100 mL, 3-neck round bottom flask, equipped with mechanical stirrer,temperature probe and nitrogen inlet was charged with cesium carbonate(654 mg, 2.01 mmol),N-(3-chloro-1-(pyridin-3-yl)-1H-pyrazol-4-yl)-3-((3,3,3-trifluoropropyl)thio)propanamide(380 mg, 1.00 mmol) and N,N-dimethylformamide, (5 mL). Iodoethane (0.089mL, 1.10 mmol) was added dropwise. The reaction was stirred at 40° C.for 2 hours, at which point thin layer chromatography analysis[((Eluent: ethyl acetate] indicated that only a trace of startingmaterial remained. The reaction mixture was cooled to 20° C. and water(20 mL) was added. It was extracted with ethyl acetate (2×20 mL) and thecombined organic layers were concentrated to dryness at <40° C. Theresidue was purified by flash column chromatography using 0-100% ethylacetate/hexane as eluent. The fractions containing pure product wereconcentrated to dryness to afford a colorless oil (270 mg, 66%): ¹H NMR(400 MHz, DMSO-d₆) δ 9.11 (d, J=2.7 Hz, 1H), 8.97 (s, 1H), 8.60 (dd,J=4.8, 1.4 Hz, 1H), 8.24 (ddd, J=8.4, 2.8, 1.4 Hz, 1H), 7.60 (ddd,J=8.4, 4.7, 0.8 Hz, 1H), 3.62 (q, J=7.1 Hz, 2H), 2.75 (t, J=7.0 Hz, 2H),2.66-2.57 (m, 2H), 2.57-2.44 (m, 2H), 2.41 (t, J=7.0 Hz, 2H), 1.08 (t,J=7.1 Hz, 3H); EIMS m/z 406 ([M]⁺).

Alternate synthetic route toN-(3-chloro-1-(pyridin-3-yl)-1H-pyrazol-4-yl)-N-ethyl-3-((3,3,3-trifluoropropyl)thio)propanamide(Compound 5.4)

To 3-neck round bottomed flask (50 mL) was added sodium hydride (60% inoil, 0.130 g, 3.28 mmol) and sulfolane (16 mL). The gray suspension wasstirred for 5 minutes thenN-(3-chloro-1-(pyridin-3-yl)-1H-pyrazol-4-yl)-3-((3,3,3-trifluoropropyl)thio)propanamide(1.20 g, 3.16 mmol) dissolved in sulfolane (25 mL) was slowly addeddropwise over 5 minutes. The mixture became a light gray suspensionafter 3 minutes and was allowed to stir for 5 minutes after which timeethyl bromide (0.800 mL, 10.7 mmol) and potassium iodide (0.120 g, 0.720mmol) were added sequentially. The cloudy suspension was then allowed tostir at room temperature. The reaction was quenched after 6 hours bybeing poured drop-wise into cooled ammonium formate/acetonitrilesolution (30 mL). The resulting orange colored solution was stirred andtetrahydrofuran (40 mL) was added. The mixture was assayed, usingoctanophenone as a standard, and found to contain (1.09 g, 85%) of thedesired product with a selectivity versus the retro-Michael-likedecomposition product of 97:3.

Example 6N-(3-chloro-1-(pyridin-3-yl)-1H-pyrazol-4-yl)-N-ethyl-3-((3,3,3-trifluoropropyl)sulfoxo)propanamide(Compound 6.4)

N-(3-chloro-1-(pyridin-3-yl)-1H-pyrazol-4-yl)-N-ethyl-3-(3,3,3-trifluoropropyl)thio)propanamide (57.4 g, 141 mmol) was stirred in methanol (180 mL). To theresulting solution was added hydrogen peroxide (43.2 mL, 423 mmol)dropwise using a syringe. The solution was stirred at room temperaturefor 6 hours, at which point LCMS analysis indicated that the startingmaterial was consumed. The mixture was poured into dichloromethane(CH₂Cl₂, 360 mL) and washed with aqueous sodium carbonate (Na₂CO₃). Theorganic layer was dried over sodium sulfate and concentrated to providethick yellow oil. The crude product was purified by flash columnchromatography using 0-10% methanol/ethyl acetate as eluent and the purefractions were combined and concentrated to afford the desired productas an oil (42.6 g, 68%): ¹H NMR (400 MHz, DMSO-d₆) δ 9.09 (dd, J=2.8,0.7 Hz, 1H), 8.98 (s, 1H), 8.60 (dd, J=4.7, 1.4 Hz, 1H), 8.24 (ddd,J=8.4, 2.7, 1.4 Hz, 1H), 7.60 (ddd, J=8.4, 4.7, 0.8 Hz, 1H), 3.61 (q,J=7.4, 7.0 Hz, 2H), 3.20-2.97 (m, 2H), 2.95-2.78 (m, 2H), 2.76-2.57 (m,2H), 2.58-2.45 (m, 2H), 1.09 (t, J=7.1 Hz, 3H); ESIMS m/z 423 ([M+H]⁺).

Example PE-1 Prophetic Preparation of(2,2-difluorocyclopropyl)methanethiol

To a solution of 2-(bromomethyl)-1,1-difluorocyclopropane (about 1equivalent) in a solvent, such as methanol (at a concentration rangingfrom about 0.01 M to about 1 M), at temperatures between about 0° C. andabout 40° C. may be added thioacetic acid (about 1 equivalent to about 2equivalents), and a base, such as potassium carbonate (about 1equivalent to 2 equivalents). An additional amount of a base, such aspotassium carbonate (about 1 equivalent to 2 equivalents) may be addedafter a time ranging from about 30 minutes to 2 hours to the mixture toremove the acyl group. The reaction may be stirred until it isdetermined to be complete. The product may then be obtained usingstandard organic chemistry techniques for workup and purification.

Alternative prophetic preparation of(2,2-difluorocyclopropyl)methanethiol

To a solution of 2-(bromomethyl)-1,1-difluorocyclopropane (about 1equivalent) in a solvent, such as methanol (at a concentration rangingfrom about 0.01 M to about 1 M), at temperatures between about 0° C. andabout 40° C. may be added thioacetic acid (about 1 equivalent to about 2equivalents), and a base, such as potassium carbonate (about 1equivalent to 2 equivalents). The intermediate thioester product maythen be obtained using standard organic chemistry techniques for workupand purification. To the thioester (about 1 equivalent) in a solvent,such as methanol (at a concentration ranging from about 0.01 M to about1 M), at temperatures between about 0° C. and about 40° C. may be addeda base, such as potassium carbonate (about 1 equivalent to 2equivalents). The reaction may be stirred until it is determined to becomplete. The product may then be obtained using standard organicchemistry techniques for workup and purification.

BIOLOGICAL EXAMPLES Example a Bioassays on Green Peach Aphid (“GPA”)(Myzus persicae) (MYZUPE

GPA is the most significant aphid pest of peach trees, causing decreasedgrowth, shriveling of leaves, and the death of various tissues. It isalso hazardous because it acts as a vector for the transport of plantviruses, such as potato virus Y and potato leafroll virus to members ofthe nightshade/potato family Solanaceae, and various mosaic viruses tomany other food crops. GPA attacks such plants as broccoli, burdock,cabbage, carrot, cauliflower, daikon, eggplant, green beans, lettuce,macadamia, papaya, peppers, sweet potatoes, tomatoes, watercress andzucchini among other plants. GPA also attacks many ornamental crops suchas carnations, chrysanthemum, flowering white cabbage, poinsettia androses. GPA has developed resistance to many pesticides.

Several molecules disclosed herein were tested against GPA usingprocedures described below.

Cabbage seedling grown in 3-in pots, with 2-3 small (3-5 cm) trueleaves, were used as test substrate. The seedlings were infested with20-5-GPA (wingless adult and nymph stages) one day prior to chemicalapplication. Four posts with individual seedlings were used for eachtreatment. Test compounds (2 mg) were dissolved in 2 mL ofacetone/methanol (1:1) solvent, forming stock solutions of 1000 ppm testcompound. The stock solutions were diluted 5× with 0.025% Tween 20 inwater to obtain the solution at 200 ppm test compound. A hand-heldaspirator-type sprayer was used for spraying a solution to both sides ofthe cabbage leaves until runoff. Reference plants (solvent check) weresprayed with the diluent only containing 20% by volume acetone/methanol(1:1) solvent. Treated plants were held in a holding room for three daysat approximately 25° C. and ambient relative humidity (RH) prior tograding. Evaluation was conducted by counting the number of live aphidsper plant under a microscope. Percent Control was measured by usingAbbott's correction formula (W. S. Abbott, “A Method of Computing theEffectiveness of an Insecticide” J. Econ. Entomol 18 (1925), pp.265-267) as follows.

Corrected % Control=100*(X−Y)/X

-   -   where    -   X=No. of live aphids on solvent check plants and    -   Y=No. of live aphids on treated plants

The results are indicated in the table entitled “Table 1: GPA (MYZUPE)and sweetpotato whitely-crawler (BEMITA) Rating Table”.

Example B Bioassays on Sweetpotato Whitefly Crawler (Bemisia tabaci)(BEMITA.)

The sweetpotato whitefly, Bemisia tabaci (Gennadius), has been recordedin the United States since the late 1800s. In 1986 in Florida, Bemisiatabaci became an extreme economic pest. Whiteflies usually feed on thelower surface of their host plant leaves. From the egg hatches a minutecrawler stage that moves about the leaf until it inserts itsmicroscopic, threadlike mouthparts to feed by sucking sap from thephloem. Adults and nymphs excrete honeydew (largely plant sugars fromfeeding on phloem), a sticky, viscous liquid in which dark sooty moldsgrow. Heavy infestations of adults and their progeny can cause seedlingdeath, or reduction in vigor and yield of older plants, due simply tosap removal. The honeydew can stick cotton lint together, making it moredifficult to gin and therefore reducing its value. Sooty mold grows onhoneydew-covered substrates, obscuring the leaf and reducingphotosynthesis, and reducing fruit quality grade. It transmittedplant-pathogenic viruses that had never affected cultivated crops andinduced plant physiological disorders, such as tomato irregular ripeningand squash silverleaf disorder. Whiteflies are resistant to manyformerly effective insecticides.

Cotton plants grown in 3-inch pots, with 1 small (3-5 cm) true leaf,were used at test substrate. The plants were placed in a room withwhitely adults. Adults were allowed to deposit eggs for 2-3 days. Aftera 2-3 day egg-laying period, plants were taken from the adult whiteflyroom. Adults were blown off leaves using a hand-held Devilbliss sprayer(23 psi). Plants with egg infestation (100-300 eggs per plant) wereplaced in a holding room for 5-6 days at 82° F. and 50% RH for egg hatchand crawler stage to develop. Four cotton plants were used for eachtreatment. Compounds (2 mg) were dissolved in 1 mL of acetone solvent,forming stock solutions of 2000 ppm. The stock solutions were diluted10× with 0.025% Tween 20 in water to obtain a test solution at 200 ppm.A hand-held Devilbliss sprayer was used for spraying a solution to bothsides of cotton leaf until runoff. Reference plants (solvent check) weresprayed with the diluent only. Treated plants were held in a holdingroom for 8-9 days at approximately 82° F. and 50% RH prior to grading.Evaluation was conducted by counting the number of live nymphs per plantunder a microscope. Insecticidal activity was measured by using Abbott'scorrection formula (sec above) and presented in Table 1.

TABLE 1 GPA (MYZUPE) and sweetpotato whitefly-crawler (BEMITA) RatingTable Example Compound BEMITA MYZUPE 1a B B 4a B D Compound 3.4 B BCompound 4.4 B A Compound 5.4 A A Compound 6.4 A A % Control ofMortality Rating 80-100 A More than 0-Less than 80 B Not Tested C Noactivity noticed in this bioassay D

COMPARATIVE EXAMPLES Example CE-1 N-(1-acetyl-1H-pyrazol-4-yl)acetamide

A 250-mL 3-neck flask was charged with 1H-pyrazol-4-amine (5 g, 60.2mmol) and dichloromethane (50 mL). The resulting suspension was cooledto 5° C. and triethylamine (TEA, 9.13 g, 90.0 mmol) was added, followedby acetic anhydride (Ac₂O, 7.37 g, 72.2 mmol) at <20° C. The reactionwas stirred at room temperature for 18 h, at which point thin layerchromatography [Eluent: ethyl acetate] analysis indicated that thereaction was incomplete. Additional triethylamine (4.57 g, 45.0 mmol)and acetic anhydride (3.70 g, 36.0 mmol) were added and the reaction washeated at 30° C. for an additional 3 hours to give a dark solution, atwhich point thin layer chromatography analysis indicated that only atrace of starting material remained. The reaction mixture was purifiedby flash column chromatography using ethyl acetate as eluent. Thefractions containing pure product were combined and concentrated todryness to afford an off-white solid. The solid was dried under vacuumat room temperature for 18 hours (5.55 g, 55%): ¹H NMR (400 MHz,DMSO-d₆) δ 10.30 (s, 1H), 8.39 (d, J=0.7 Hz, 1H), 7.83 (d, J=0.7 Hz,1H), 2.60 (s, 3H), 2.03 (s, 3H); EIMS m/z 167 ([M]⁺).

Example CE-2 N-(3-Bromo-1H-pyrazol-4-yl)acetamide

A 250 mL 3-neck round bottom flask was charged with1H-pyraz-4-amine.hydrobromide (4.00 g, 24.7 mmol) and water (23 mL). Tothe mixture, sodium bicarbonate (8.30 g, 99.0 mmol) was added slowlyover 10 minutes, followed by tetrahydrofuran (23 mL). The mixture wascooled to 5° C. and acetic anhydride (2.60 g, 25.4 mmol) was added over30 minutes while maintaining the internal temperature at <10° C. Thereaction mixture was stirred at ˜5° C. for 20 minutes, at which point ¹HNMR and UPLC analyses indicated that the starting material was consumedand the desired product as well as bis-acetylated byproduct were formed.The reaction was extracted with ethyl acetate and the organic layerswere dried over magnesium sulfate (MgSO₄) and concentrated. The crudemixture was triturated with methyl tert-butylether (MTBE) to remove thebisacetylated product to afford ˜1.24 g of a white solid. ¹H NMRanalysis showed it was 1:1.1 desired to undesired bisacetylated product.The solid was purified by flash column chromatography using 50-100%ethyl acetate/hexanes as eluent to afford the desired product as a whitesolid (380 mg, 7.5%) and the bisacetylated product as a white solid(˜800 mg): ¹H NMR (400 MHz, DMSO-d₆) δ 13.01 (s, 1H), 9.36 (s, 1H), 7.92(s, 1H), 2.03 (s, 3H); ¹³C NMR (101 MHz, DMSO-d₆) δ 167.94, 123.93,119.19, 119.11, 22.63; ESIMS m/z 204 ([M+H]⁺).

Example CE-3 Alkylation Versus Retro-Michael-Like Decomposition

A suspension of sodium hydride (60% in oil, 1.03 equivalent) and solvent(1 vol) was stirred for 5 minutes.N-(3-Chloro-1-(pyridin-3-yl)-1H-pyrazol-4-yl)-3-((3,3,3-trifluoropropyl)thio)propanamide(1 equivalent) dissolved in solvent (2 vol) was slowly added dropwiseover 5 minutes. Ethyl bromide (3.3 equivalents) and additive (0.22equivalents) were added sequentially. The suspension was then allowed tostir at room temperature until consumption of starting material wasobserved. The selectivity of Compound 6.3 over the decomposition productwas determined by HPLC (See Table 2).

TABLE 2 Compound 6.3: Decompo- Time sition Entry Additive Solvent(hours) Product 1 tetrabutylammonium N,N- 24 81:19 iodide dimethyl-formamide 2 potassium iodide N,N- 72 94:6  dimethyl- formamide 3potassium iodide N-methyl- 20 92:8  pyrolidinone

It should be understood that while this invention has been describedherein in terms of specific embodiments set forth in detail, suchembodiments are presented by way of illustration of the generalprinciples of the invention, and the invention is not necessarilylimited thereto. Certain modifications and variations in any givenmaterial, process step or chemical formula will be readily apparent tothose skilled in the art without departing from the true spirit andscope of the present invention, and all such modifications andvariations should be considered within the scope of the claims thatfollow.

1-10. (canceled)
 11. A process of applying a compound of the formula

to a locus to control insects. 12.-17. (canceled)